Synthesis and antioxidant properties of some novel 1,3,4,2-oxadiazaphosphepino[6,7-c]quinolinones and pyrazolo[3,4:4′,3′]quinolino[5,1-c][1,4,2]oxazaphosphinine

Article abstract of DOI:10.1080/10426507.2017.1290625

A series of novel 1,3,4,2-oxadiazaphosphepino[6,7-c]quinolinones 3–5, 9, and 11 have been synthesized from treatment of 4-hydroxy-1-methyl-3-[1-(2-phenylhydrazinylidene)ethyl]quinolin-2(1H)-one (2) with some phosphorus sulfides, diethyl phosphite and phen

Full text of DOI:10.1080/10426507.2017.1290625

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis and antioxidant properties of
some novel 1,3,4,2-oxadiazaphosphepino[6,7-
c]quinolinones and pyrazolo[3,4:4′,3′]quinolino[5,1-
c][1,4,2]oxazaphosphinine
Mohamed M. Hassan, Somaia M. Abdel-Kariem & Tarik E. Ali
To cite this article: Mohamed M. Hassan, Somaia M. Abdel-Kariem & Tarik E. Ali (2017):
Synthesis and antioxidant properties of some novel 1,3,4,2-oxadiazaphosphepino[6,7-
c]quinolinones and pyrazolo[3,4:4′,3′]quinolino[5,1-c][1,4,2]oxazaphosphinine, Phosphorus, Sulfur,
and Silicon and the Related Elements, DOI: 10.1080/10426507.2017.1290625
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1290625
Accepted author version posted online: 27
Mar 2017.
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Date: 30 March 2017, At: 04:48

ACCEPTED MANUSCRIPT
Synthesis and antioxidant properties of some novel 1,3,4,2-oxadiazaphosphepino[6,7-
c]quinolinones and pyrazolo[3,4:4`,3`]quinolino[5,1-c][1,4,2]oxazaphosphinine
*
Mohamed M. Hassan , Somaia M. Abdel-Kariem and Tarik E. Ali
Department of Chemistry, Faculty of Education, Ain Sham University, Cairo, Egypt
*
Corresponding author E-mail: mmhassan121@yahoo.com
ABSTRACT
A series of novel 1,3,4,2-oxadiazaphosphepino[6,7-c]quinolinones 3–5, 9 and 11 have been
synthesized
from
treatment
of
4-hydroxy-1-methyl-3-[1-(2-phenyl-
hydrazinylidene)ethyl]quinolin-2(1H)-one (2) with some phosphorus sulfides, diethyl phosphite
and phenyl phosphonic dichloride, respectively, in dry dioxane. Also, reaction of hydrazone 2
with
tris(2-chloroethyl)phosphite
under
the
same
reaction
conditions
gave
pyrazolo[3,4:4`,3`]quinolino[5,1-c][1,4,2]oxazaphosphinine 10. However, when hydrazone 2
was treated with phosphonic acid, phosphorus tribromide or phosphorus oxychloride, 3,5-
dimethyl-1-phenyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (7) was isolated in all cases.
The compounds were evaluated for their antioxidant activities. Among the synthesized
compounds, 1,3,4,2-oxadiazaphosphepino[6,7-c]quinolinone-2-sulfide 5 and its analogue 2-
oxide 11 exhibited higher antioxidant activities than the standard antioxidant.
Ph
Y
X
Ph
N
Ph
P
N
Ph
NH
OH
N
O
O
N
N
O
N
N
P reagents
CH3
P
CH
3
CH3
Me
O
OH
O
N
N
O
N
N
CH3
CH3
CH3
CH
3
X=O, S
Y=H, SH, EtO, Ph, 4-MeC H4
6
1
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Keywords
Quinolinone; hydrazone; oxadiazaphosphepine; oxazaphosphinine; antioxidant
2
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INTRODUCTION
2
-Quinolinone compounds are class of bioactive heterocyclic systems, which received
1
,2
much attention due to their important pharmacological activities such as antioxidant, anti-
3
-7
inflammatory, antimalarial, antimicrobial and anticancer properties. Phosphorus compounds
have also received increasing attention in the last years due to their wide range of applications in
8
,9
medicinal and organic chemistry. In particular, phosphorus heterocycles have broad biological
1
0-13
activities such as anticancer, antimicrobial, analgesic and anti-inflammatory activity.
Due to
synthetic and biological values of 2-quinolinones and phosphorus heterocycles, we expected that
the combination of phosphorus heterocycles with 2-quinolinone moiety in one molecular frame
may lead to enhanced biological properties. However, to the best of our knowledge, synthesis of
phosphorus heterocycles derived from 4-hydroxy-2-quinolinone has not been reported in the
literature. Our recent work has involved the synthesis of bioactive phosphorus compounds
1
4-16
bearing heterocycles.
The target of the present research is the synthesis of novel phosphorus
heterocycles containing 2-quinolinone system, and investigates their potential antioxidant
properties.
RESULT AND DISCUSSION
Chemistry
4
-Hydroxy-1-methyl-3-[1-(2-phenylhydrazinylidene)ethyl]quinolin-2-(1H)-one (2) was
obtained by reaction of 3-acetyl-4-hydroxyquinolin-2(1H)-one (1) with phenylhydrazine in
1
7,18
dimethylformamide in excellent yield (Scheme 1).
The hydrazone 2 was used as starting material to construct some novel phosphorus
heterocycles linked to 2-quinolinone ring via its treatment with some phosphorus reagents. Thus,
3
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treatment of hydrazone 2 with phosphorus pentasulfide, O,O-diethyldithiophosphoric acid and
Lawesson’s reagent (LR) in dry dioxane under reflux furnished the corresponding 1,3,4,2-
oxadiazaphosphepino[6,7-c]quinolinones 3–5, respectively (Scheme 2). The structures of
compounds 3–5 were supported on the basis of their elemental analyses and spectral data. Their
-1
IR spectra showed absorption bands in regions 1656–1664 and 756–812 cm ascribed to C=O
and P=S functionalities. In addition, the absence of bands for OH and NH groups confirmed the
1
cyclization process with participation of the phosphorus atom. Also, their H NMR spectra
supported the suggested structures. The SH proton in compound 3 and the methoxy protons in
compound 5 were observed at δ 3.45 and 3.78 ppm, respectively, while the ethoxy protons of
1
3
compound 4 appeared at δ 1.21–1.29 ppm (CH ) and 4.00–4.20 ppm (CH ). In their C NMR
3
2
spectra, the most important signals in the range δ 12.7–12.8, 28.6 and 158.2–158.3 ppm, were
assigned to CH , NCH and C=O, respectively. Furthermore, the NMR signals for the carbon
3
3
atoms of the ethoxy and methoxy groups in compounds 4 and 5 were observed at δ 16.6, 59.5
3
1
and 55.2 ppm, respectively. The P NMR spectrum of compound 5 showed a singlet at δ 61.1
ppm. The mass spectra displayed the corresponding molecular ion peaks at m/z 401, 413 and
4
75, respectively.
As an extension of this study, the behavior of hydrazone 2 towards phosphonic acid,
diethylphosphite and tris(2-chloroethyl)phosphite, was also investigated. Thus, reaction of
hydrazone 2 with phosphonic acid in dry dioxane containing 4-toluenesulfonic acid as a catalyst
under Pudovik reaction conditions, did not give the expected α-hydrazinophosphonic acid 6
(Scheme 3). Instead 3,5-dimethyl-1-phenyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (7)
1
9
was formed (Scheme 3). The formation of compound 7 instead of 6 may be due to the
4
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preference of hydrazone 2 to cyclize than to react with the phosphorus reagent. The presence of
strong acidic medium using phosphonic acid and 4-toluenesulfonic acid may facilitate the
1
8
cyclization process.
o
Similarly, when the hydrazone 2 was treated with diethyl phosphite at 80–90 C in the
2
0
presence of BF3 etherate under Pudovik reaction conditions
oxadiazophosphepino[6,7-c]quinolinone 9A,B and not the α-hyrazinophosphonate 8 was formed
Scheme 3). The suggested mechanism for the formation of compound 9 is a cyclization of
unexpectedly the
(
hydrazone 2 via the nucleophilic attack of NH and OH groups at phosphorus atom and
elimination of two molecules of ethanol. The IR spectrum of compound 9 revealed the absence
-1
of NH group and the appearance of absorption bands at 3289, 1287 and 1657 cm assigned to P–
OH, P=O and C=O groups, respectively. The mass spectrum of compound 9 displayed its
+
1
molecular ion peak M in agreement with its molecular formula. The H NMR spectrum revealed
the P–H proton as a doublet resonating at δ 6.70 ppm with a P,H coupling constant of 630 Hz, as
3
1
well as the other expected signals. Its P NMR spectrum showed two signals at δ 7.6 ppm (form
1
31
9
A) and 16.1 ppm (form 9B). The IR, H and P NMR spectra confirmed the presence of
21
compound 9 in two tautomeric forms because of phosphite-phosphonate tautomerism.
The novel cyclic phosphonic ester 10 was obtained via reaction of hydrazone 2 with tris(2-
chloroethyl)phosphite under the same reaction conditions (Scheme 4). A plausible mechanism
for formation of product 10 may start with a Michael addition of the phosphite to the azomethine
bond to give the non isolatable intermediate D, which undergoes cyclization via nucleophilic
attack of NHPh at position 4 of the quinoline ring to eliminate a water molecule affording the
pyrazolyl intermediate E. The latter non isolatable intermediate undergoes another cyclization
5
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via elimination of hydrogen chloride, followed by acid-catalyzed hydrolysis to afford the final
2
2
product (Scheme 4). Its IR spectrum showed the specific absorption bands at 3395 (P–OH),
-1
1
1
660 (C=O) and 1289 cm (P=O). Also its H NMR spectrum displayed three specific signals at
δ 2.75, 4.21 and 5.50 ppm ascribed to NCH , OCH and P–OH protons, respectively, as well as
2
2
13
multiplets at δ 6.98–7.79 ppm assigned to nine aromatic protons. Furthermore, its C NMR
spectrum showed signals at δ 15.9, 36.4 and 158.1 ppm, which were assigned to NCH , OCH
2
2
3
1
and C=O, respectively. Its P NMR spectrum showed a singlet at δ 13.1 ppm. The mass
spectrometry was an excellent tool to prove the proposed structure and showed its molecular ion
peak at m/z 397.
The reactivity of hydrazone 2 towards some phosphorus halides was also investigated.
Thus, heterocyclization of hydrazone 2 with phenyl phosphonic dichloride in dry dioxane
containing
two
equivalents
of
triethylamine
yielded
the
corresponding
oxadiazaphosphepinoquinolinone 11 in good yield (Scheme 5). The IR spectrum of 11 showed
-1
the presence of bands at 1658 (C=O) and 1270 (P=O) cm , and the absence of the bands for NH
1
13
and OH groups of hydrazone 2. Its H and C NMR spectra confirmed the presence of five
additional aromatic protons and six additional carbon atoms due to presence of the Ph-P=O
3
1
moiety, whereas its P NMR spectrum displayed a singlet at δ 34.2 ppm. The mass spectrum
+
showed its molecular ion peak M at m/z 429.
Finally, when hydrazone 2 was allowed to react with equimolar amounts of phosphorus
tribromide or phosphorus oxychloride in dry dioxane containing two equivalents of triethylamine
the previously described compound 7 (Scheme 3) was formed. The suggested mechanism for the
formation of compound 7 in this case, may involve a halogenation process via the phosphorus
6
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halide at position 4 of the quinolinone ring, followed by cyclization via dehydrohalogenation
1
8
with the help of triethylamine affording the final product 7 in high yield (Scheme 5).
Antioxidant activity
The antioxidant properties of the synthesized compounds were evaluated by two in vitro
methods in order to compare the results and to establish some structure-antioxidant activity
relationships. The evaluation study was carried out at various concentrations at 50, 75 and 100
g/mL. DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging activity evaluation is a
standard assay in antioxidant activity studies and offers a rapid technique for screening the
2
3,24
radical scavenging activity of specific compounds or extracts.
A freshly prepared DPPH
solution exhibits a deep purple colour with an absorption maximum at 517 nm. This purple
colour generally disappears when an antioxidant is present in the medium. Thus, antioxidant
molecule can quench DPPH free radical (i.e., by providing hydrogen atoms or electrons) and
convert it to a colorless product (i.e., 2,2-diphenyl-1-picrylhydrazine), resulting in a decrease of
absorbance. Hence, more rapidly the absorbance decrease, the more potent the antioxidant
activity of the compound. Percentage activity of ethanolic solutions of the synthesized
compounds was examined and compared (Table S 1 Supplemental Materials).. The antioxidant
activity of β-carotenoid is based on its radical adducts with free radicals from linoleic acid. The
linoleic acid free radical attacks the highly unsaturated β-carotene model. The presence of
antioxidants can decrease the extent of β-carotene bleaching by neutralizing the linoleate-free
2
5
radical and other free radicals formed in the system. Accordingly, the absorbance decreases
rapidly in the samples without an antioxidant, whereas in the presence of an antioxidant, they
retain the colour for a longer time. The percentage (%) antioxidant activity of newly synthesized
7
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compounds under study is shown in Table S 2 (Supplemental Materials). The 50 % inhibitory
concentration IC towards DPPH activity of newly synthesized compounds was also calculated
5
0
(Table S 3). We can conclude from the results that the synthesized compounds showed
promising radical scavenging abilities according to the two methods used and compared with
ascorbic acid as standard antioxidant. The results revealed that most of the compounds exhibited
good radical scavenging abilities at lower concentrations. However, the gradual increase in the
activity in all cases was observed with increase in the concentrations of the test compounds. It
was perceived that compounds 2, 7 and 10 exhibited moderate activities, whereas 3, 4 and 9
displayed good antioxidant properties. It is clear that the presence of phosphorus heterocycles
especially with the oxadiazaphosphepine ring enhanced the antioxidant properties in comparison
with the other compounds
2
and 7. Among the tested compounds, the
oxadiazaphosphepinoquinolinones 5 and 11 were the most potential antioxidant agents. This may
be due to effective conjugation as well as presence of methoxy group as electron donating group.
EXPERIMENTAL
Melting points were determined in an open capillary tube with a digital Stuart SMP-3
apparatus. Infrared spectra were measured with a FT-IR (Nicolet IS10) spectrophotometer and a
1
13
Perkin-Elmer 293 spectrophotometer using KBr disks. H and C NMR spectra were measured
with a Gemini-300 BB spectrometer at 300 MHz and 75 MHz, respectively, using DMSO-d as
6
3
1
solvent and TMS as an internal standard. P NMR spectra were obtained with a Bruker
spectrometer at 242 MHz and at room temperature using DMSO-d as a solvent and 85 % H PO
4
6
3
as external reference. Mass spectra were recorded with a Gas Chromatographic GCMSqp 1000
ex Shimadzu instrument at 70 eV. Elemental microanalyses were performed with a Perkin-Elmer
8
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2
400II instrument at the Chemical War Department, Ministry of Defense. The purity of the
synthesized compounds was checked by thin layer chromatography (TLC) and elemental
microanalyses. The starting material 4-hydroxy-1-methyl-3[1-(2-phenyl-
hyrazinylidene)ethyl]quinolin-2(1H)-one (2) was prepared as described in the literature.
Synthesis of 5,7-dimethyl-3-phenyl-2-sulfanyl-2-sulfido-3,7-dihydro[1,3,4,2]oxa-
1
7
diazaphosphepino[6,7-c]quinolin-6(2H)-one (3)
A mixture of phosphorus pentasulfide (1.11 g, 5 mmol) and compound 2 (1.53 g, 5 mmol)
in dry dioxane (50 mL), was heated under reflux for 10 h. The reaction mixture was concentrated
to half of its volume and left to cool down to ambient temperature. The solid formed was filtered
off and recrystallized from ethanol to give an orange crystalline solid in 43 % yield; mp 180−182
-1
°
C. IR (KBr), (max, cm ): 3056 (C–Harom), 2930 (C–Haliph), 1656 (C=O), 1615 (C=N), 1597
1
(
C=C), 1095 (P–O–C), 756 (P=S). H NMR (300 MHz, DMSO-d ): δ = 2.56 (s, 3H, CH ), 3.45
6
3
(
br, 1H, P–SH exchangeable with D O), 3.58 (s, 3H, NCH ), 6.99–7.08 (m, 2H, Ar–H), 7.51–
2 3
1
3
7
.67 (m, 5H, Ar–H), 7.90 (d, J = 7.0 Hz, 1H, H–11). C NMR (75 MHz, DMSO-d ): δ = 12.7
6
(
CH ), 28.6 (NCH ), 110.3 (C–5a), 111.1 (C–8), 116.2 (C–11a), 120.5 (C–10), 121.4 (C–4`phenyl),
3 3
1
1
22.1 (C–11), 127.1 (C–2`,6`phenyl), 129.8 (C–3`,5`phenyl), 130.1 (C–9), 139.1 (C–7a), 140.0 (C–
+
`phenyl), 147.6 (C–5), 150.0 (C–11b), 158.2 (C=O). MS (m/z): 401 (M ). Anal. Calcd. for
C H N O PS (401.44): C, 53.85; H, 4.02; N, 10.47; S, 15.97. Found: C, 53.49; H, 3.82; N,
18
16
3
2
2
1
0.08 S, 15.62 %.
9
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Synthesis
of
5,7-dimethyl-2-ethoxy-3-phenyl-2-sulfido-3,7-dihydro[1,3,4,2]oxa-
diazaphosphepino[6,7-c]quinolin-6(2H)-one (4)
A solution of phosphorus pentasulfide (1.11 g, 5 mmol) in absolute ethanol (30 mL) was
heated under reflux for 1 h. A solution of compound 2 (1.53 g, 5 mmol) in dry dioxane (30 mL)
was added to this ethanolic solution. The mixture was heated under reflux for 8 h. The reaction
mixture was concentrated to half of its volume and left to cool down to ambient temperature. The
solid formed after adding of some water (10 mL), was filtered off and recrystallized from dilute
-1
DMF to give a beige crystalline solid in 80 % yield; mp 163−164 °C. IR (KBr), (max, cm ):
3
8
056 (C–Harom), 2935, 2885 (C–Haliph) 1659 (C=O), 1617 (C=N), 1574 (C=C), 1091 (P–O–C),
1
12 (P=S). H NMR (300 MHz, DMSO-d ): δ = 1.21–1.29 (m, 3H, CH ), 2.56 (s, 3H, CH ), 3.57
6
3
3
(
s, 3H, NCH ), 4.00–4.20 (m, 2H, OCH ), 6.87–7.67 (m, 8H, Ar–H), 8.04 (d, J = 6.9 Hz, 1H, H–
3 2
1
3
1
1). C NMR (75 MHz, DMSO-d ): δ 12.7 (CH ), 16.6 (CH ), 28.6 (NCH ), 59.5 (OCH ), 111.1
6 3 3 3 2
(C–5a), 112.6 (C–8), 116.1 (C–11a), 121.4 (C–4`phenlyl), 122.1 (C–10), 124.3 (C–11), 127.1 (C–
2
1
5
`,6`phenyl), 129.8 (C–3`,5`phenyl), 132.0 (C–9), 139.2 (C–7a), 140.0 (C–1`phenyl), 145.0 (C–5),
+
47.6 (C–11b), 158.2 (C=O). MS (m/z): 413 (M ). Anal. Calcd. for C H N O PS (413): C,
2
0
20
3
3
8.10; H, 4.88; N, 10.16; S, 7.76. Found: C, 57.69; H, 4.55; N, 9.88; S, 7.39 %.
of 5,7-dimethyl-2-(4-methoxyphenyl)-3-phenyl-2-sulfido-3,7-dihydro-
1,3,4,2]oxadiazaphosphepino[6,7-c]quinolin-6(2H)-one(5)
Lawesson's reagent (1.6 g, 4 mmol) was added to a solution of compound 2 (1.23 g, 4
Synthesis
[
mmol) in dry dioxane (50 mL). The mixture was heated under reflux for 10 h. The mixture was
concentrated to half of its volume and left to cool down to ambient temperature. The solid
obtained was filtered off and recrystallized from dilute ethanol to give an orange solid in 53 %
10
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-1
yield; mp 205−207 °C. IR (KBr), (max, cm ): 3055 (C–Harom), 2981, 2923 (C–Haliph), 1664
1
(
C=O), 1618 (C=N), 1598 (C=C), 1095, 1079 (O–C), 773 (P=S). H NMR (300 MHz, DMSO-
d ): δ = 2.58 (s, 3H, CH ), 3.61 (s, 3H, NCH ), 3.78 (s, 3H, OCH ), 6.97–7.07 (m, 5H, Ar–
6
3
3
3
1
3
H),7.53–7.67 (m, 8H, Ar–H). C NMR (75 MHz, DMSO-d ): δ = 12.8 (CH ), 28.6 (NCH ), 55.2
6
3
3
(OCH ), 110.4 (C–5a), 111.2 (C–8), 113.4 (C–3``,5`` ), 116.2 (C–11a), 120.7 (C–10), 121.5
3 aryl
(
C–4`phenyl), 122.2 (C–11), 124.1, 126.6 (C–2``,6`` ), 127.1 (C–2`,6`phenyl), 129.8 (C–3`,5`phenyl),
aryl
1
1
30.2 (C–9), 132.3 (d, JPC = 9.5 Hz, C–1`` ), 139.7 (C–7a), 140.1 (C–1`phenyl), 147.7 (C–5),
aryl
3
1
50.0 (C–11b), 158.3 (C=O), 161.2 (C–4`` ). P NMR (240 MHz, DMSO-d ): δ = 61.1 ppm.
aryl
6
+
MS (m/z): 475 (M ). Anal. Calcd. for C H N O PS (475.49): C, 63.15; H, 4.66; N, 8.84; S,
2
5
22
3
3
6
.74. Found: C, 62.83; H, 4.23; N, 8.49;S, 6.37 %.
Synthesis of 3,5-dimethyl-1-phenyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (7)
Method A: Phosphonic acid (0.82 g, 10 mmol) was added to a solution of compound 2 (1.53 g, 5
mmol) in dry dioxane (60 mL) in presence of a catalytic amount of 4-toluenesulfonic acid (0.1
g). The mixture was heated under reflux for 12 h. The reaction mixture was concentrated to half
of its volume. After adding of some water (30 mL), the solid formed was filtered off and
crystallized from dilute ethanol to give a yellow crystalline solid in 57 % yield; mp 190−192 °C
1
8
(
Lit. mp 190−193 °C).
Method B: A solution of phosphorus tribromide (0.5 mL, 5 mmol) in dry dioxane (5 mL), was
added dropwise to a solution of compound 2 (1.53 g, 5 mmol) in dry dioxane (60 mL) in
presence of a catalytic amount of triethylamine (0.7 mL, 10 mmol) at 5−10 °C during 30 min.
The mixture was heated under reflux for 10 h. After adding of some water (30 mL) the solid
11
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formed was filtered off and crystallized from dilute ethanol to give a yellow solid in 60 % yield;
mp 189−192 °C.
Method C: A solution of phosphorus oxychloride (0.5 mL, 5 mmol) in dry dioxane (5 mL), was
added dropwise to a solution of compound 2 (1.53 g, 5 mmol) in dry dioxane (60 mL) in
presence of a catalytic amount of triethylamine (0.7 mL, 10 mmol) at 5−10 °C during 30 min.
The mixture was heated under reflux for 10 h. The reaction mixture was concentrated to half of
its volume and left to cool down to ambient temperature. After adding of some water (30 mL) the
solid formed was filtered off and crystallized from dilute ethanol to give a yellow solid in 75 %
-1
yield; mp 192−194 °C. IR (KBr), (max, cm ): 3051 (C–Harom), 2980, 2918 (C–Haliph), 1658
1
(
C=O), 1616 (C=N), 1595 (C=C). H NMR (300 MHz, DMSO-d ): δ = 2.56 (s, 3H, CH ), 3.59
6
3
1
3
(
s, 3H, NCH ), 7.01–7.09 (m, 2H, Ar–H), 7.53–7.67 (m, 7H, Ar–H). C NMR (75 MHz,
3
DMSO-d ): δ = 12.7 (CH ), 28.6 (NCH ), 110.3 (C–3a), 111.2 (C–6), 116.2 (C–9a), 120.7 (C–8),
6
3
3
1
21.4 (C–4`phenyl), 122.1 (C–9), 127.1 (C–2`,6`phenyl), 129.8 (C–3`,5`phenyl), 130.1 (C–7), 140.0
(
(
C–9b), 139.6 (C–5a), 139.2 (C–1`phenyl), 147.6 (C–3), 158.2 (C=O). Anal. Calcd. for C H N O
18
15
3
289.33): C, 74.72; H, 5.23; N, 14.52. Found: C, 74.48; H, 4.96; N, 14.17 %.
Synthesis of 5,7-dimethyl-2-oxido-3-phenyl-3,7-dihydro[1,3,4,2]oxadiaza-phosphepino[6,7-
c]quinolin-6(2H)-one (9A) and 5,7-dimethyl-2-hydroxy-3-phenyl-3,7-
dihydro[1,3,4,2]oxadiazaphosphepino[6,7-c]quinolin-6(2H)-one (9B)
A mixture of diethyl phosphite (1.4 mL, 10 mmol) and compound 2 (1.53 g, 5 mmol) in
presence of BF etherate (0.1 mL) as a catalyst was allowed to react on a water bath for 6 h. The
3
reaction mixture was treated with cold water to give a solid, which was filtered off and
recrystallized from dilute ethanol to yield a beige solid in 59 % yield; mp 201−203 °C. IR (KBr),
12
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-1
(
max, cm ): δ = 3289 (br, OH), 3054 (C–Harom), 2922 (C–Haliph), 1657 (C=O), 1617 (C=N), 1596
1
(
C=C), 1287 (P=O), 1096 (P–O–C). H NMR (300 MHz, DMSO-d ): δ = 2.57 (s, 3H, CH ), 3.61
6
3
(
s, 3H, NCH ), 4.22 (br, 1H, P–OH exchangeable with D O), 6.70 (d, 1H, J = 630 Hz, P–H),
3
2
1
3
7
.02–7.10 (m, 2H, Ar–H), 7.53–7.67 (m, 6H, Ar–H), 7.90 (d, J = 7.0 Hz, 1H, H–11). C NMR
(
75 MHz, DMSO-d ): δ = 12.7 (CH ), 28.6 (NCH ), 110.5 (C–5a), 111.2 (C–8), 116.2 (C–11a),
6 3 3
1
20.5 (C–10), 121.5 (C–4`phenyl), 122.1 (C–11), 127.1 (C–2`,6`phenyl), 129.8 (C–3`,5`phenyl), 130.1
3
1
(
C–9), 139.2 (C–7a), 139.8 (C–1`phenyl), 147.6 (C–5), 152.0 (C–11b), 158.2 (C=O). P NMR (240
+
MHz, DMSO-d ): δ = 7.6 and 16.1 ppm. MS (m/z): 353 (M ). Anal. Calcd. for C H N O P
6
18 16
3
3
(353.31): C, 61.19; H, 4.56; N, 11.89. Found: C, 60.79; H, 4.18; N, 11.61 %.
Synthesis
of
11,12b-dimethyl-1-hydroxy-1-oxido-6-phenyl-3,4,11,12b-tetrahydro-
pyrazolo[3,4:4`,3`]quinolino[5,1-c][1,4,2]oxazaphosphinin-12(6H)-one (10)
A mixture of tris(2-chloroethyl)phosphite (2.7 mL, 10 mmol) and compound 2 (1.53 g, 5
mmol) in presence of BF etherate (0.1 mL) as a catalyst, were allowed to react on a water bath
3
for 8 h (0.2 mL of distilled water added after 2 h). The reaction mixture was treated with cold
water to give the solid which was filtered off and recrystallized from dilute ethanol to yield a
-1
beige solid in 77 % yield; mp 223−225 °C (dec.). IR (KBr), (max, cm ): 3395 (OH), 3053 (C–
1
Harom), 2952 (C–Haliph), 1660 (C=O), 1599 (C=C), 1289 (P=O), 1099 (P–O–C). H NMR (300
MHz, DMSO-d ): δ = 2.45 (s, 3H, CH ), 2.75 (s, 2H, CH N), 3.55 (s, 3H, NCH ), 4.21 (s, 2H,
6
3
2
3
OCH ), 5.50 (br, 1H, P–OH exchangeable with D O), 6.98–7.15 (m, 3H, Ar–H), 7.49–7.67 (m,
2
2
1
3
5
H, Ar–H). C NMR (75 MHz, DMSO-d ): δ = 12.7 (CH ), 15.9 (NCH ), 28.5 (NCH ), 36.4
6 3 2 3
(
OCH ), 110.3 (C–12a), 112.1 (d, J = 142.3 Hz, C–12b), 116.1 (C–10), 117.9 (C–6b), 121.4 (C–
2
8
), 122.2 (C–4`phenyl), 123.5 (C–7), 127.1 (C–2`,6`phenyl), 129.9 (C–3`,5`phenyl), 130.4 (C–9), 139.3
13
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3
1
(
C–10a), 139.8 (C–1`phenyl), 140.1 (C–6a), 158.1 (C=O). P NMR (240 MHz, DMSO-d ): δ =
6
+
1
1
3.1 ppm. MS (m/z): 397 (M ). Anal. Calcd. for C H N O P (397.36): C, 60.45; H, 5.07; N,
20 20 3 4
0.57. Found: C, 60.11; H, 4.73; N, 10.19 %.
of 5,7-dimethyl-2,3-diphenyl-2-oxido-3,7-dihydro[1,3,4,2]oxadiaza-
Synthesis
phosphepino[6,7-c]quinolin-6(2H)-one (11)
A solution of phenyl phosphonic dichloride (0.7 mL, 5 mmol) in dry dioxane (5 mL), was
added dropwise to a solution of compound 2 (1.53 g, 5 mmol) in dry dioxane (50 mL) in
presence of a catalytic amount of triethylamine (0.7 mL, 10 mmol) at 5−10 °C during 30 min.
The mixture was heated under reflux for 4 h and then filtered off to remove the triethyl
ammonium chloride. The filtrate was concentrated to half of its volume and left standing at
ambient temperature. The solid formed was filtered off, washed with cold water and
recrystallized from dilute ethanol to give the product as beige solid in 78 % yield; mp 200−203
-1
°
C.IR (KBr), (max
,
cm ): 3097, 3050 (C–Harom), 2980, 2918 (C–Haliph), 1658 (C=O), 1616
1
(
C=N), 1595 (C=C), 1095 (P–O–C), 1270 (P=O). H NMR (300 MHz, DMSO-d ): δ = 2.56 (s,
6
3
H, CH ), 3.58 (s, 3H, NCH ), 7.00–7.08 (m, 2H, Ar–H), 7.51–7.65 (m, 4H, Ar–H), 7.89–7.92
3 3
1
3
(
m, 4H, Ar–H), 8.08–8.12 (m, 4H, Ar–H). C-NMR (75 MHz, DMSO-d ): δ = 12.7 (CH ), 28.6
6 3
(
NCH ), 110.4 (C–5a), 111.1 (C–8), 114.5 (C–2
ꢀ
,6
ꢀ
), 115.8 (C–4"phenyl), 116.1 (C–11a),
3
phenyl
1
20.6 (C–3
ꢀ
,5
ꢀ
), 120.7 (C–10), 121.4 (C–4`phenyl), 122.1 (C–11), 127.1 (C–2`,6`phenyl), 129.8
phenyl
(C–3`,5`phenyl), 130.0 (C–9), 133.9 (d, JPC = 10 Hz, C–1"phenyl), 139.6 (C–7a), 140.0 (C–1`phenyl),
3
1
1
47.6 (C–5), 149.5 (C–11b), 158.2 (C=O). P NMR (240 MHz, DMSO-d ): δ = 34.2 ppm. MS
6
+
(
m/z): 429 (M ). Anal. Calcd. for C H N O P (429.40): C, 67.13; H, 4.69; N, 9.79. Found: C,
2
4
20
3
3
6
6.84; H, 4.31; N, 9.43 %.
14
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Antioxidant activity
DPPH radical scavenging activity
The DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging effect was determined
2
3,24
according to the reported method.
One milliliter solution of various concentrations of the test
compounds (50, 75, and 100 g/mL) in ethanol were added to 4 mL of 0.004 % (w/v) ethanol
solution of DPPH. The tubes were then incubated in the dark room at RT for 30 min. A DPPH
blank was prepared without compound, and ethanol was used for the baseline correction.
Changes (decrease) in the absorbance at 517 nm were measured using a UV-Vis
spectrophotometer. The radical scavenging activities were expressed as the inhibition percentage
and were calculated using the formula: % radical scavenging activity = (AB–AA)/AB × 100
where AB = absorption of blank and AA = absorption of the tested compound. The radical
scavenging activity of ascorbic acid was also measured and compared with that of the different
synthesized compound. The compound concentration providing 50 % inhibition (IC ) was
5
0
calculated.
Antioxidant activity by β-carotene-linoleic acid assay
Each compound at the final concentrations of 50, 75, and 100 g/mL was incorporated into
β-carotene-linoleic acid model system independently and the activity was monitored
25
spectrophotometrically at 470 nm. The substrate suspension was prepared by addition of β-
carotene (4 mg dissolved in 5 mL of chloroform) to a covered round bottomed flask containing
Tween-40 (600 mg) followed by the addition of linoleic acid (60 mL). The chloroform was
removed completely under vacuum using rotary evaporator at 40 °C. The resulting solution was
diluted with triple distilled water (30 mL) and the emulsion was mixed well and diluted with
15
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oxygenated water (120 mL). The aliquot (4 mL) was transferred to different stopper test tubes
containing compounds in distilled ethanol. Control was prepared with distilled ethanol (1 mL)
and emulsion (4 mL). Ascorbic acid solution as internal standard of the same concentration was
also analyzed for comparison. Zero adjustment was done using distilled water. As soon as the
emulsion was added to each test tube, the zero time (t = 0) absorbance was measured at 470 nm
using spectrophotometer and subsequently absorbance was measured for every 30 min up to 3 h
(t = 180) time interval. The tubes were placed in a water bath at 50 °C between the readings.
Percentage antioxidant activities of each compound were evaluated in triplicates in terms of
photooxidation of β-carotene using the following formula:
%
antioxidant activity = 100 × {1- (A –A /A –A )}
o t oo to
where: A = Initial absorbance of the sample. (t = 0 min)
o
A = Absorbance of the sample after time ‘t’. (t = 180 min)
t
A = Initial absorbance of the control. (t = 0 min)
oo
A = Absorbance of control after time ‘t’. (t =180 min)
to
Acknowledgments
The authors are very grateful to the Faculty of Pharmacy, Al-Azhar University, Nasr-City,
Cairo, Egypt, for performing the antioxidant evaluation.
16
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REFERENCES
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2
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. Oliveira, F. M.; Barbosa, L. C.; Ismail, F. M. RSC Adv. 2014, 4, 18998–19012.
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1
2. Abdou, W. M.; Barghash, R. F.; Bekheit, M. S. J. Arch. Pharm. Chem. Life Sci. 2012, 345,
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6. Abdel-Rahman, R. M.; Ali, T. E.; Abdel-Kariem, S. M. Arkivoc 2016, i, 183–211.
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Ph
OH
O
O
NH
OH
N
O
CH3
PhNHNH2
CH3
N
DMF
N
CH3
1
CH3
2
Scheme 1 Synthesis of hydrazone 2
19
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SH
Ar
S
N
+
S
S
P
P
NH
N
N
OH
N
N
O
OH
N
O
OH
CH3
LR
CH3 P S5
CH3
2
Dioxane
Dioxane
N
N
O
CH3
CH3
CH3
A
2
C
Dioxane [(EtO) P(S)SH]
2
-
H S
3`
1`
4`
6`
2
5
`
OEt
EtO
HS
S
MeO
3``
3`
4`
S
P
4
``
P
N
3
2
`` 2`
5
`
2
N
1
O
N4
5
``
OH
N
N
O
1
``
S
1`
11
1
1b
6
`
11a
5
1
0
6
``
P
N
3
2
CH3
5a
CH3
1
O
N4
9
7
1
1
11b
7
a
N
6
O
1
1a
5
8
1
0
9
5
a
CH3
CH3
CH3
7
7
a
N
6
O
3
B
8
CH3
-
EtOH
5
3
`
4`
Ar = 4-MeOC H
6
4
5
`
EtO
S
1`
6
`
S
S
S
S
S
S
P
N
3
2
P S
P
S
P
+ P
S
P +
1
O
N4
2
5
1
1
S
S
11b
1
1a
5
1
0
S
S
S
S
5a
CH3
Ar=4-MeOC H4
9
7
Ar
P
P
S
Ar
2
Ar P+
6
S
7a
N
6
O
8
LR
CH3
4
Scheme 2 Reaction of hydrazone 2 with sulfur containing phosphorus reagents
20
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H
O
O
P
N
N
3`
4`
2`
1`
CH3
1
2
5`
N
N
3
N
O
6`
9
9b
9
a
3a
NH
8
7
CH3
CH3
OH
N
O
H PO3
4
9
A
HP(O)(OEt)2
BF .Et O
3
5
5
a
N
O
CH3
6
Dioxane
4-TsOH
3
`
3
2
CH3
2
`
Fusion
4
`
N
7
HO
2
3
5`
CH3
2
P
N
1`
1
6`
O
N
4
11
1
1b
1
1a
5
1
0
NH
P
5a
CH3
OH HN
OH
O
7
9
7a
N
6
O
8
NH
P
OH
CH3
CH3
OH HN
OEt
O
N
O
9
B
OEt
CH3
CH3
N
O
6
CH3
8
Scheme 3 Reaction of hydrazone 2 with phosphonic acid and diethyl phosphite
21
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NH
OH
N
O
NH
P
Cl
OH HN
O
O
P(OCH CH Cl)
3
CH3
2
2
BF .Et O
O
CH3
3
2
N
Fusion
Cl
CH3
2
N
O
CH3
D
-
H O Cyclization
2
H
Cl
N
N
O
P
O
O
CH3
Cl
N
O
CH3
E
5
`
4
`
6`
HCl Cyclization
-
4
1
6
5
3
`
1
`
N
N
3
2
`
7
Addiing few drops
6
a
12b
N N
6
b
O 2
H O after 1 h.
8
2
P
1
2a
O
P
Me OH
Cl
9
11
O
O
Hydrolysis
Me
O
O
1
0a
N
12
1
0
O
N
CH3
CH3
1
0
F
Scheme 4 Reaction of hydrazone 2 with tris(2-chloroethyl)phosphite
22
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5
`
6
`
4`
Ph O 3 1`
NH
OH
N
O
N
3
`
P
N
X
N
N
O
2
2`
1
O
N 4
5
i or ii
1
1b
PhP(O)Cl2
CH3
1
1
CH3
1
1a
5a
1
0
9
i, PBr
, dioxane, Et N
3
Dioxane
3
CH3
N
7
Et N
3
ii, POCl , dioxane, Et N
3 3
7
a
N
6
O
CH3
8
CH3
CH3
G
2
1
1
X = Br, Cl - HX
N
N
O
CH3
N
CH3
7
Scheme 5 Reaction of hydrazone 2 with PhP(O)Cl , PBr and POCl
3
2
3
23
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